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Overview: The Cellular Internet • Cell-to-cell communication is essential for multicellular organisms • Biologists have discovered some universal mechanisms of cellular regulation • The combined effects of multiple signals determine cell response • For example, the dilation of blood vessels is controlled by multiple molecules Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Evolution of Cell Signaling • A signal transduction pathway is a series of steps by which a signal on a cell’s surface is converted into a specific cellular response • Signal transduction pathways convert signals on a cell’s surface into cellular responses Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Local and Long-Distance Signaling • Cells in a multicellular organism communicate by chemical messengers • Animal and plant cells have cell junctions that directly connect the cytoplasm of adjacent cells • In local signaling, animal cells may communicate by direct contact, or cell-cell recognition Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Fig. 11-4 Plasma membranes Gap junctions between animal cells (a) Cell junctions (b) Cell-cell recognition Plasmodesmata between plant cells Fig. 11-2 factor Receptor 1 Exchange of mating factors a a factor Yeast cell, mating type a 2 Mating 3 New a/ cell Yeast cell, mating type a a/ Fig. 11-3 1 Individual rodshaped cells 2 Aggregation in process 0.5 mm 3 Spore-forming structure (fruiting body) Fruiting bodies • In many other cases, animal cells communicate using local regulators, messenger molecules that travel only short distances • In long-distance signaling, plants and animals use chemicals called hormones Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Fig. 11-5 Long-distance signaling Local signaling Electrical signal along nerve cell triggers release of neurotransmitter Target cell Secreting cell Local regulator diffuses through extracellular fluid (a) Paracrine signaling Endocrine cell Neurotransmitter diffuses across synapse Secretory vesicle Target cell is stimulated Blood vessel Hormone travels in bloodstream to target cells Target cell (b) Synaptic signaling (c) Hormonal signaling The Three Stages of Cell Signaling: A Preview • Earl W. Sutherland discovered how the hormone epinephrine acts on cells • Sutherland suggested that cells receiving signals went through three processes: – Reception – Transduction – Response Animation: Overview of Cell Signaling Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Fig. 11-6-1 EXTRACELLULAR FLUID 1 Reception Receptor Signaling molecule CYTOPLASM Plasma membrane Fig. 11-6-2 CYTOPLASM EXTRACELLULAR FLUID Plasma membrane 1 Reception 2 Transduction Receptor Relay molecules in a signal transduction pathway Signaling molecule Fig. 11-6-3 CYTOPLASM EXTRACELLULAR FLUID Plasma membrane 1 Reception 2 Transduction 3 Response Receptor Activation of cellular response Relay molecules in a signal transduction pathway Signaling molecule Concept 11.2: Reception: A signal molecule binds to a receptor protein, causing it to change shape • The binding between a signal molecule (ligand) and receptor is highly specific • A shape change in a receptor is often the initial transduction of the signal • Most signal receptors are plasma membrane proteins Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Receptors in the Plasma Membrane • Most water-soluble signal molecules bind to specific sites on receptor proteins in the plasma membrane • There are three main types of membrane receptors: – G protein-coupled receptors – Receptor tyrosine kinases – Ion channel receptors Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings • A G protein-coupled receptor is a plasma membrane receptor that works with the help of a G protein • The G protein acts as an on/off switch: If GDP is bound to the G protein, the G protein is inactive Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Fig. 11-7b Plasma membrane G protein-coupled receptor Activated receptor Signaling molecule GDP CYTOPLASM GDP Enzyme G protein (inactive) GTP 2 1 Activated enzyme GTP GDP Pi Cellular response 3 4 Inactive enzyme 15.3 How Is a Response to a Signal Transduced through the Cell? Studies with human bladder cancer cells: • They have an abnormal form of a G protein called Ras. The protein was permanently bound to GTP, causing continuous cell division. • Ras was thought to be an intermediary between binding of growth factor to receptor, and the cell’s response. • Receptor tyrosine kinases are membrane receptors that attach phosphates to tyrosines • A receptor tyrosine kinase can trigger multiple signal transduction pathways at once Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Fig. 11-7c Ligand-binding site Signaling molecule (ligand) Signaling molecule Helix Tyrosines Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Receptor tyrosine kinase proteins CYTOPLASM Dimer 1 2 Activated relay proteins Tyr Tyr Tyr Tyr P Tyr P Tyr Tyr Tyr P 6 ATP Activated tyrosine kinase regions 6 ADP Tyr Tyr P Tyr Tyr P Tyr P Tyr P Tyr Tyr P P P P Tyr P Tyr Fully activated receptor tyrosine kinase Inactive relay proteins 3 4 Cellular response 1 Cellular response 2 • A ligand-gated ion channel receptor acts as a gate when the receptor changes shape • When a signal molecule binds as a ligand to the receptor, the gate allows specific ions, such as Na+ or Ca2+, through a channel in the receptor Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Fig. 11-7d 1 Signaling molecule (ligand) Gate closed Ligand-gated ion channel receptor 2 Ions Plasma membrane Gate open Cellular response 3 Gate closed Intracellular Receptors • Some receptor proteins are intracellular, found in the cytosol or nucleus of target cells • Small or hydrophobic chemical messengers can readily cross the membrane and activate receptors • Examples of hydrophobic messengers are the steroid and thyroid hormones of animals • An activated hormone-receptor complex can act as a transcription factor, turning on specific genes Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Fig. 11-8-2 ormone estosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein UCLEUS CYTOPLASM Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormonereceptor complex DNA DNA NUCLEUS CYTOPLASM Concept 11.3: Transduction: Cascades of molecular interactions relay signals from receptors to target molecules in the cell • Signal transduction usually involves multiple steps • Multistep pathways can amplify a signal: A few molecules can produce a large cellular response • Multistep pathways provide more opportunities for coordination and regulation of the cellular response Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Signal Transduction Pathways • The molecules that relay a signal from receptor to response are mostly proteins • Like falling dominoes, the receptor activates another protein, which activates another, and so on, until the protein producing the response is activated • At each step, the signal is transduced into a different form, usually a shape change in a protein Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Protein Phosphorylation and Dephosphorylation • In many pathways, the signal is transmitted by a cascade of protein phosphorylations • Protein kinases transfer phosphates from ATP to protein, a process called phosphorylation Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Fig. 11-9 Signaling molecule Receptor Activated relay molecule Inactive protein kinase 1 Active protein kinase 1 Inactive protein kinase 2 ATP ADP Pi P Active protein kinase 2 PP Inactive protein kinase 3 Pi ATP ADP Active protein kinase 3 PP Inactive protein P ATP P ADP Pi PP Active protein Cellular response Termination of the Signal • Inactivation mechanisms are an essential aspect of cell signaling • When signal molecules leave the receptor, the receptor reverts to its inactive state Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings • Protein phosphatases remove the phosphates from proteins, a process called dephosphorylation • This phosphorylation and dephosphorylation system acts as a molecular switch, turning activities on and off Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Small Molecules and Ions as Second Messengers • The extracellular signal molecule (the first messenger) that binds to the receptor can also generate a second messenger along the pathway • Second messengers are small, nonprotein, water-soluble molecules or ions that spread throughout a cell by diffusion • Second messengers participate in pathways initiated by G protein-coupled receptors and receptor tyrosine kinases Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings • The second messenger carries the signal from the membrane receptor to the cytoplasm. • Second messengers affect many cell processes, amplifying the signal. They are short life molecules • Some of the most well known second messengers are: • cAMP • IP3 and DAG • Ca++ • Nitric Oxide (NO) Fig. 11-10 Adenylyl cyclase Phosphodiesterase Pyrophosphate P ATP Pi cAMP AMP Fig. 11-11 First messenger Adenylyl cyclase G protein G protein-coupled receptor GTP ATP cAMP Second messenger Protein kinase A Cellular responses Calcium Ions and Inositol Triphosphate (IP3) • Calcium ions (Ca2+) act as a second messenger in many pathways • Calcium is an important second messenger because cells can regulate its concentration Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Fig. 11-12 EXTRACELLULAR FLUID Plasma membrane Ca2+ pump ATP Mitochondrion Nucleus CYTOSOL Ca2+ pump Endoplasmic reticulum (ER) ATP Key High [Ca2+] Low [Ca2+] Ca2+ pump • A signal relayed by a signal transduction pathway may trigger an increase in calcium in the cytosol • Pathways leading to the release of calcium involve inositol triphosphate (IP3) and diacylglycerol (DAG) as additional second messengers Animation: Signal Transduction Pathways Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Fig. 11-13-3 EXTRACELLULAR FLUID Signaling molecule (first messenger) G protein DAG GTP G protein-coupled receptor PIP2 Phospholipase C IP3 (second messenger) IP3-gated calcium channel Endoplasmic reticulum (ER) CYTOSOL Various proteins activated Ca2+ Ca2+ (second messenger ) Cellular responses Figure 15.13 The IP3/DAG Second-Messenger System Concept 11.4: Response: Cell signaling leads to regulation of transcription or cytoplasmic activities • The cell’s response to an extracellular signal is sometimes called the “output response” Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Nuclear and Cytoplasmic Responses • Ultimately, a signal transduction pathway leads to regulation of one or more cellular activities • The response may occur in the cytoplasm or may involve action in the nucleus • Many signaling pathways regulate the synthesis of enzymes or other proteins, usually by turning genes on or off in the nucleus • The final activated molecule may function as a transcription factor Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Fig. 11-14 Growth factor Reception Receptor Phosphorylatio n cascade Transduction CYTOPLASM Inactive transcription factor Active transcription factor P Response DNA Gene NUCLEUS mRNA Other pathways regulate the activity of enzymes Figure 15.14 A Signal Transduction Pathway Leads to the Opening of Ion Channels (Part 1) Figure 15.14 A Signal Transduction Pathway Leads to the Opening of Ion Channels (Part 2) • Signaling pathways can also affect the physical characteristics of a cell, for example, cell shape Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Fig. 11-16 RESULTS ∆Fus3 Wild-type (shmoos) ∆formin CONCLUSION 1 Mating factor G protein-coupled receptor Shmoo projection forming Formin P Fus3 GTP GDP Phosphorylation cascade 2 Actin subunit P Formin Formin P 4 Fus3 Fus3 P Microfilament 5 3 Signal Transduction • Advantages of signal transduction pathway: – Amplification: One molecule of receptor, activated 100 molecules of second meesenger which activates 1000 molecules of effecor proteins down the cascade and so on. – Specificity: Only a specific signal at the cell membrane is transferred inside the cell. – Provide more opportunities of regulation: Having many steps affecting different target proteins also allows for a variety of responses by different cells to the same signal. Fig. 11-15 Reception Binding of epinephrine to G protein-coupled receptor (1 molecule) Transduction Inactive G protein Active G protein (102 molecules) Inactive adenylyl cyclase Active adenylyl cyclase (102) ATP Cyclic AMP (104) Inactive protein kinase A Active protein kinase A (104) Inactive phosphorylase kinase Active phosphorylase kinase (105) Inactive glycogen phosphorylase Active glycogen phosphorylase (106) Response Glycogen Glucose-1-phosphate (108 molecules) The Specificity of Cell Signaling and Coordination of the Response • Different kinds of cells have different collections of proteins • These different proteins allow cells to detect and respond to different signals • Even the same signal can have different effects in cells with different proteins and pathways • Pathway branching and “cross-talk” further help the cell coordinate incoming signals Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Fig. 11-17 Signaling molecule Receptor Relay molecules Response 1 Cell A. Pathway leads to a single response. Response 2 Response 3 Cell B. Pathway branches, leading to two responses. Activation or inhibition Response 4 Cell C. Cross-talk occurs between two pathways. Response 5 Cell D. Different receptor leads to a different response. Fig. 11-UN1 1 Reception 2 Transduction 3 Response Receptor Relay molecules Signaling molecule Activation of cellular response